iit cti bendamustine, rituximab, pixantrone in relapsed/refractory b cell non-hodgkin's lymphoma

Conditions: Non-Hodgkin's Lymphoma

Summary: this is a phase i trial of the combination of bendamustine, rituximab and pixantrone in patients with relapsed/refractory b cell non-hodgkin lymphoma. a standard 3+3 design will be used to determine the maximum tolerated dose (mtd) of the combination. a static dose of bendamustine and rituximab will be used and the dose of pixantrone will be escalated in each cohort. pixantrone will be dosed on a 21 day cycle at 55mg/m2, 85mg/m2, and 115mg/m2 in sequential cohorts dependent on acceptable toxicity profile at each dose level. mtd will be determined based on dlts that occur during the first 2 cycles of the drug combination. phase ii did not proceed as planned due to withdrawal of pixantrone from the us.

this is a phase i trial utilizing a traditional 3+3 design to evaluate maximum tolerated dose (mtd) and optimal dose schedule of pixantrone in combination with bendamustine (120mg/m2 on day 1 of each 21 day cycle) and rituximab (375mg/m2 on day 1 of each 21 day cycle). no patients will be entered on an escalated dosage level until at least 3 patients have been treated at the previous level and assessed for a dose limiting toxicity. dose levels will be escalated in cohorts of 3 patients as long as no drug-related dlt occurs in the first 2 cycles. if one patient is observed to suffer a dlt, this cohort will be expanded to include at least 6 patients total. if less than 2 patients in the expanded cohort of 6 patients experience a dlt, dose escalation will resume. if 2 of 6 patients enrolled at the same dose level experience a dlt, the mtd has been exceeded, and the dose escalation will cease. the next lower dose will be considered the mtd. if any patient withdraws from the study prior to completing 2 cycles for reasons other than a dlt then that patient will be replaced in order to determine the mtd. if dose limiting toxicity is observed at the initial dose level in 2 patients, the mtd has been exceeded and the starting dose level will be reduced to 25mg/m2. if 1 patient experiences a dlt in the -1 dose range, the cohort will be expanded to at least 6 patients. if a second patient experiences a dlt at the -1 dose level, the trial will be closed. for part 1, those who have a confirmed diagnosis of relapsed/refractory b cell non-hodgkin's lymphoma of any subtype will be considered eligible for enrollment. each cycle will be 21 days. subjects will be assessed for dlts during the first 2 cycles of study drug. they will be assessed for response after cycle 2. patients not experiencing a dlt during the first 2 cycles and who have stable disease or better may continue to receive up to 6 cycles of treatment with the triplet combination. if any patient withdraws from the study prior to completing 2 cycles for reasons other than a dlt then that patient will be replaced in order to determine the mtd. phase ii did not proceed as planned due to withdrawal of pixantrone from the us.

Eligibility criteria:
inclusion criteria: 1. part i: subjects must have relapsed or refractory b cell nhl; 2. part ii: subjects must have relapsed or refractory aggressive b cell nhl including follicular lymphoma (fl) grade 3, diffuse large b cell lymphoma (dlbcl), transformed nhl, mantle cell lymphoma (mcl), or other aggressive b cell nhl histology as per the who 2008 criteria; 3. refractory disease (defined as persistence of evaluable disease after therapy) or relapsed disease following at least one prior treatment regimen that should include autologous stem cell transplant unless a patient was not eligible or refused prior transplant; 4. age ≥ 18 years old; 5. eastern cooperative oncology group (ecog) performance status of ≤2; 6. subjects must have measurable or evaluable disease based on physical exam and/or radiographs (ct, mri, pet) or bone marrow involvement; 7. female subject is either post-menopausal or surgically sterilized; 8. laboratory values: * absolute neutrophil count (anc) ≥ 1.5 x 10\^9/l; lower levels accepted if due to marrow involvement by lymphoma * platelets ≥ 75,000/mcl; lower levels accepted if due to marrow involvement by lymphoma * total bilirubin ≤ 1.5 x institutional upper limit of normal; ≤ 3.0 uln accepted in subjects with gilbert's syndrome * ast/alt ≤ 1.5 x institutional upper limit of normal. subjects with known liver involvement by lymphoma: ast/alt ≤ 2 x institutional upper limit of normal * serum creatinine \< 1.5 x institutional upper limit of normal 9. ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed exclusion criteria: 1. no chemotherapy, radiation, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received bcnu or mitomycin c). 2. no radioimmunotherapy within 2 months prior to registration. 3. subjects receiving chronic, systemic treatment with corticosteroids equivalent to \> 20mg of prednisone per day. subjects receiving replacement for adrenal insufficiency will be allowed on the study. topical or inhaled corticosteroids are allowed. 4. subjects with a history of another primary malignancy ≤ 3 years ago, with the exception of inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a psa that has not increased for at least 3 months, carcinoma in situ of the cervix. 5. major surgery ≤ 4 weeks prior to registration. minor surgery ≤ 2 weeks prior to registration. insertion of a vascular access device is not considered major or minor surgery. subjects must have recovered from all surgery related toxicities to ≤ grade 1 or to baseline if subject started with \> grade 1 toxicity, not otherwise violating the above inclusion criteria. 6. subjects who have received investigational drugs ≤ 4 weeks prior to registration. 7. impaired cardiac function: * qtc \> 480 on screening ecg. * previous history of angina pectoris or acute mi within 6 months * congestive heart failure (new york heart association functional classification iii-iv) or baseline muga/echo shows estimated lvef \< 45% * any history of torsade de pointes, ventricular fibrillation, uncontrolled ventricular tachycardia, or uncontrolled atrial fibrillation. 8. female patients who are pregnant or breastfeeding 9. patients with history of untreated hepatitis b or who are known carriers of hepatitis b will be excluded from this trial. all subjects will be screened prior to study entry. 10. concurrent use of other anti-cancer agents or anti-cancer treatments.